Biallelic variants in GTF3C3 encoding a subunit of the TFIIIC2 complex are associated with neurodevelopmental phenotypes in humans and zebrafish

Abdel-Hamid, Mohamed S; Paimboeuf, Adeline; Zaki, Maha S; Figueiredo, Fernanda; Abdel-Ghafar, Sherif F; Maher, Sabrina; Friðriksdóttir, Run; Sulem, Patrick; Högnason, Hákon Björn; Hallgrímsdóttir, Sigrun; Rojas, Catarina Falleiros N; Kok, Fernando; Suri, Mohnish; Alves, César Augusto P F; Houlden, Henry; Maroofian, Reza et Patten, Shunmoogum A. ORCID: https://orcid.org/0000-0002-2782-3547 (2025). Biallelic variants in GTF3C3 encoding a subunit of the TFIIIC2 complex are associated with neurodevelopmental phenotypes in humans and zebrafish Brain Communications , vol. 7 , nº fcaf055. pp. 1-13. DOI: 10.1093/braincomms/fcaf055.

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Résumé

RNA polymerase III transcribes essential non-coding RNAs, a process regulated by transcription factors TFIIIB and TFIIIC. Although germline variants in TFIIIC subunit genes have been described in a few patients with neurodevelopmental disorders, the associated pathogenesis and clinical spectrum are not yet well defined. Herein, we describe the identification of biallelic variants in GTF3C3, which encodes a key component of the TFIIIC subunit, in four patients from three unrelated families of different ethnicities collected through GeneMatcher. The patients exhibited microcephaly, developmental delay, intellectual disability and distinctive dysmorphic facies that appear recognizable in very young children. Their brain imaging showed brain atrophy with predominant cerebellar involvement, as well as hypoplasia of the frontal lobes and one patient had moderate to severe simplified gyral pattern. Seizures were observed in half of the patients. Exome/genome sequencing revealed four different GTF3C3 variants including three missense (p.Cys172Gly, p.Val427Phe and p.Ala509Thr) and one nonsense variant (p.Arg717Ter). Missense variants were not present in known genetic databases and occurred in highly conserved residues. Knockout of the GTF3C3 ortholog in zebrafish recapitulated the key clinical symptoms including microcephaly, brain anomalies and seizure susceptibility. We also observed reduced RNA polymerase III target gene expression in the zebrafish knockout model. This study describes a new neurodevelopmental syndrome in humans and zebrafish associated with biallelic GTF3C3 variants and underscores the need for further research into the biological impacts of variants in TFIIIC-linked genes and their contribution to RNA polymerase III-related pathologies.

Type de document:	Article
Mots-clés libres:	GTF3C3; RNA polymerase III; TFIIIC; neurodevelopmental disorder; zebrafish knockout
Centre:	Centre INRS-Institut Armand Frappier
Date de dépôt:	10 mars 2025 01:08
Dernière modification:	10 mars 2025 01:08
URI:	https://espace.inrs.ca/id/eprint/16357

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